OP0121 SYNOVIAL CELLULAR NICHES ARE DETERMINANTS OF ARTHRITIS PERSISTENCE VERSUS RESOLUTION IN EARLY UNTREATED ARTHRITIS
Authors: A. Filer, J. D. Turner, C. Prada-Medina, M. Attar, C. D. Buckley, S. Sansom, K. Raza
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Published synovial research largely focuses on persistent clinical syndromes such as RA and PsA. However spontaneously resolving synovitis is a common manifestation of viral infection (parvovirus, influenza), post-bacterial reactive states and metabolic disease such as gout. The study of synovial tissue taken from such patients using advanced single cell methodologies may provide biomarkers of outcome in early disease but is also a valuable resource to understand mechanisms underlying the subversion of healthy mechanisms of resolution resulting in persistent disease. <h3>Objectives</h3> To use single cell RNA sequencing to understand the cellular interactions governing resolution versus persistence of disease in untreated patients with active arthritis. <h3>Methods</h3> Synovial tissue biopsies were obtained using ultrasound guidance from treatment naïve patients in the Birmingham BEACON early arthritis cohort presenting with at least one clinically swollen joint and a joint amenable to ultrasound guided biopsy. Tissue samples from patients who went on to develop RA (n=15) or PsA (n=7) according to ACR criteria or CASPAR criteria at 24month follow-up, and patients whose arthritis spontaneously resolved (n=5) underwent enzymatic disaggregation and were processed through a multimodal single-cell sequencing approach including the characterisation of the transcriptome and 58 surface-protein-panel profile. Sequenced gene libraries were integrated according to batch and sample using the Harmony integrative algorithm before clustering and annotating cell states using canonical marker genes. Seurat-based automated pipelines were used for variable gene identification and clustering. We used DESeq2 to identify per cell type genes, and weighted gene co-expression network analysis (WGCNA) to identify gene programmes associated with persistence (RA and PSA) versus resolving groups. NAMTI was used to identify unique cellular niches associated with persistence or resolution. <h3>Results</h3> ~90,000 viable cells were sequenced and data normalised, clustered and annotated describing over 80 cellular states across eight main synovial cell types (T, B, Plasma, Plasmacytoid DC, myeloid, fibroblast, mural and vascular). A total of 1945 genes varied significantly with prognosis, distributed unequally across cell types (Table 1). <h3>Conclusion</h3> Persistence and spontaneous resolution of synovial inflammation are accompanied by characteristic compositional and mechanistic signatures that can be observed in key cellular niches during active early inflammation. There is potential to exploit such signatures with the aim of disrupting persistent inflammation. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Andrew Filer Consultant of: Janssen, Sonoma, Grant/research support from: BMS, Roche, UCB, Nascient, Mestag, GSK, Janssen, Jason D. Turner: None declared, Cesar Prada-Medina: None declared, Moustafa Attar: None declared, Christopher D Buckley: None declared, Stephen Sansom: None declared, Karim Raza Consultant of: Abbvie and Sanofi, Grant/research support from: Bristol Myers Squibb.